1. Field of the Invention
The present invention relates to a process for producing a peptide. More particularly, the invention relates to a process for producing a peptide by using a specific enzyme as a catalyst.
2. DESCRIPTION OF THE PRIOR ART
Conventional processes for producing peptides include the azide method, the mixed acid anhydride method, the carbodiimide method, the active ester method, the acid chloride method and the like. However, various industrial problems are encountered by the conventional processes, such as that racemization of the carboxyl component at the C-terminal amino acid residue occurs. Other problems include side reactions, temperature control, selection of solvent, the properties of the amino protective groups and the carboxyl protective groups and the effects of functional groups on the side chains of amino acids. In the fragment condensation method of preparing a peptide, a peptide can be divided for each fragment so as to minimize the damage caused by accidental failure and thus, the method has several industrial advantages. The fragment condensation method can be advantageously applied to compounds containing glycine (the only amino acid which can not be racemized) at the carboxyl terminal group. However, for compounds containing any other amino acid at the carboxyl terminal group, racemization cannot be prevented. In actuality, in any peptide synthesis, the racemization problem is serious. When racemization occurs, the purity of the product is decreased and it is necessary to separate the impure isomer from the product. This is very detrimental for any industrial operation.
Among the conventional methods for forming peptide bonds, the azide method is the only method in which racemization is not much of a problem, and it is for this reason that it is a desirable method. However, since the azide method involves complicated operational procedures, and because an urea derivative is produced in a side reaction thereby decreasing the yield of product, the azide method is also unsatisfactory.
In addition to the various organic chemical processes, for preparing peptides, a particular peptide synthesis using the enzyme papain or chymotrypsin has been disclosed (see, for example, J. S. Fruton "Advances in Protein Chemistry", 5, Academic Press Inc., New York, N.Y. 1949). The reactions of this method are as follows. ##STR1## The problem which is common to reactions (1) to (3) is that it is necessary to remove the phenylamino group from the peptide (III) by severe conditions because the phenyl amino group which is bonded to the C-terminal group of the amine component (II) cannot be easily separated from the peptide and thus cleavage of the peptide chain is disadvantageous. Because of this deficiency, this mode of peptide synthesis cannot be practically used for peptide synthesis. On the other hand, reaction (4) is accompanied by transamidation and transpeptidation side reactions and thus is not practically suitable. (See, for example, R. B. Johnston et al; J. Biol, Chem., 185, 629 (1950) and J. S. Fruton et al; J. Biol., Chem., 204, 891 (1953).) In reaction (4), the primary amino group of the acid amide bonded to the terminal group of the amine component, promotes the papain catalyzed amidase reaction. Accordingly, these processes provide only a theoretical interest in showing that papain and chymotrypsin act as catalysts for the synthesis of peptide bonds in which the phenylamino or a primary amino group is used as the protective group for the terminal carboxyl group of the amine component. These processes give no indication of the possibility of synthesizing a desired oligopeptides or polypeptides.